Susanne
Hiller–Sturmhöfel, Ph.D., is a science editor for Alcohol
Research & Health.

A deficiency in the
essential nutrient thiamine resulting from chronic alcohol consumption is one
factor underlying alcohol–induced brain damage. Thiamine is a helper molecule
(i.e., a cofactor) required by three enzymes involved in two pathways of carbohydrate
metabolism. Because intermediate products of these pathways are needed for the
generation of other essential molecules in the cells (e.g., building blocks
of proteins and DNA as well as brain chemicals), a reduction in thiamine can
interfere with numerous cellular functions, leading to serious brain disorders,
including Wernicke–Korsakoff syndrome, which is found predominantly in
alcoholics. Chronic alcohol consumption can result in thiamine deficiency by
causing inadequate nutritional thiamine intake, decreased absorption of thiamine
from the gastrointestinal tract, and impaired thiamine utilization in the cells.
People differ in their susceptibility to thiamine deficiency, however, and different
brain regions also may be more or less sensitive to this condition. Key
words: thiamine deficiency; alcoholic brain syndrome; chronic AODE (alcohol
and other drug effects); Wernicke’s encephalopathy; Wernicke–Korsakoff
psychosis; alcoholic cerebellar degeneration; AODR (alcohol and other drug related)
structural brain damage; malnutrition; disease susceptibility; survey of research

Alcohol consumption can
damage the brain through numerous mechanisms, many of which are discussed in
the articles in this issue of Alcohol Research & Health. One of these
mechanisms involves the reduced availability of an essential nutrient, thiamine,
to the brain as a consequence of chronic alcohol consumption. This article describes
the normal role of thiamine in brain functioning as well as the pathological
consequences that result from thiamine deficiency. Specific actions of thiamine
on a cellular level then are reviewed, followed by a discussion of how alcohol
affects the body’s processing and availability of thiamine as well as
thiamine utilization by the cells. Finally, the article explores the hypothesis
that people may differ in their sensitivity to thiamine deficiency and that
different brain regions may be more or less sensitive to a deficiency in this
important nutrient. Thiamine deficiency is particularly important because it
can exacerbate many of the other processes by which alcohol induces brain injury,
as described in other articles in this issue of Alcohol Research & Health.

WHAT IS THIAMINE
AND WHAT ARE THE CONSEQUENCES OF THIAMINE DEFICIENCY?

Thiamine, also known as
vitamin B1, is an essential nutrient required by all tissues, including
the brain. The human body itself cannot produce thiamine but must ingest it
with the diet. Thiamine–rich foods include meat (e.g., pork) and poultry;
whole grain cereals (e.g., brown rice and bran); nuts; and dried beans, peas,
and soybeans. In addition, many foods in the United States commonly are fortified
with thiamine, including breads and cereals. Humans require a minimum of 0.33
milligrams (mg) thiamine for every 1,000 kilocalories (kcal) of energy they
consume—in other words, people who consume a regular 2,000–kcal
diet per day should ingest a minimum of 0.66 mg thiamine daily (Hoyumpa 1980).
To provide a safety margin, a daily intake of 1.1 mg thiamine is currently recommended
for adult women and 1.2 mg for adult men.1 (1 Lower levels
are recommended for children, and slightly higher levels [1.4 mg thiamine per
day] are recommended for pregnant and breast–feeding women.) Studies have
found that most healthy people typically consume 0.4 to 2.0 mg thiamine daily
(Woodhill and Nobile 1972).

In the body, particularly
high concentrations of thiamine are found in skeletal muscles and in the heart,
liver, kidney, and brain (Singleton and Martin 2001). In the tissues, thiamine
is required for the assembly and proper functioning of several enzymes that
are important for the breakdown, or metabolism, of sugar molecules into other
types of molecules (i.e., in carbohydrate catabolism). Proper functioning of
these thiamine–using enzymes is required for numerous critical biochemical
reactions in the body, including the synthesis of certain brain chemicals (i.e.,
neurotransmitters); production of the molecules making up the cells’ genetic
material (i.e., nucleic acids); and production of fatty acids, steroids, and
certain complex sugar molecules. In addition, inadequate functioning of the
thiamine–using enzymes can interfere with the body’s defense against
the damage (i.e., oxidative stress) caused by harmful, highly reactive oxygen
molecules called free radicals. (For more information, see the section “Thiamine’s
Actions in the Cell.”)

Because thiamine and the
thiamine–using enzymes are present in all cells of the body, it would
be plausible that inadequate thiamine affects all organ systems; however, the
cells of the nervous system and heart seem particularly sensitive to the effects
of thiamine deficiency. Therefore, the resulting impairment in the functioning
of the thiamine–using enzymes primarily affects the cardiovascular and
nervous systems. The classical manifestations of thiamine deficiency–related
heart disease include increased blood flow through the vessels in the body,
heart failure, and sodium and water retention in the blood. In the brain, thiamine
is required both by the nerve cells (i.e., neurons) and by other supporting
cells in the nervous system (i.e., glia cells). Thiamine deficiency is the established
cause of an alcohol–linked neurological disorder known as Wernicke–Korsakoff
syndrome (WKS), but it also contributes significantly to other forms of alcohol–induced
brain injury, such as various degrees of cognitive impairment, including the
most severe, alcohol–induced persisting dementia (i.e., “alcoholic
dementia”). These disorders are discussed in the following sections.

Wernicke’s
Encephalopathy and Korsakoff’s Psychosis

WKS typically consists of
two components, a short–lived and severe condition called Wernicke’s
encephalopathy (WE) and a long–lasting and debilitating condition known
as Korsakoff’s psychosis. WE is an acute life–threatening neurologic
disorder caused by thiamine deficiency. In affluent countries, where people
normally receive adequate thiamine from their diets, thiamine deficiency is
most commonly caused by alcoholism (Singleton and Martin 2001); accordingly,
in these countries WE is primarily found in alcoholics (Ragan et al. 1999).
The symptoms of WE include mental confusion, paralysis of the nerves that move
the eyes (i.e., oculomotor disturbances), and an impaired ability to coordinate
movements, particularly of the lower extremities (i.e., ataxia). For example,
patients with WE may be too confused to find their way out of a room or may
not even be able to walk. Many WE patients, however, do not exhibit all three
of these signs and symptoms, and clinicians working with alcoholics must be
aware that WE may be present even if the patient presents with only one or two
of them. In fact, neuropathological studies after death indicate that many cases
of thiamine deficiency–related encephalopathy may not be diagnosed in
life because not all the “classic” signs and symptoms are present
or recognized.

Approximately 80 to 90 percent
of alcoholics with WE develop Korsakoff’s psychosis, a chronic neuropsychiatric
syndrome characterized by behavioral abnormalities and memory impairments (Victor
et al. 1989). Although these patients have problems remembering old information
(i.e., retrograde amnesia), it is the disturbance in acquisition of new information
(i.e., anterograde amnesia) that is most striking. For example, these patients
can engage in a detailed discussion of events in their lives but cannot remember
ever having had that conversation an hour later. Because of these characteristic
memory deficits, Korsakoff’s psychosis also is called alcohol amnestic
disorder. It is still somewhat controversial, however, whether Korsakoff’s
psychosis always is preceded by WE or whether it develops in fits and starts,
without an overt episode of WE.

The role of thiamine in
the development of WKS is supported by findings that giving this nutrient to
patients with WKS reverses many of the acute symptoms of the disease, although
in some people certain chronic neuropsychiatric consequences of previous thiamine
deficiency may persist even with appropriate treatment (see Singleton and Martin
2001). In the most severe cases, these persistent symptoms meet the criteria
of full–blown Korsakoff’s psychosis. Other people may exhibit more
subtle neurological signs and symptoms, such as abnormalities in a brain region
called the cerebellum (as described in the following section) and an inflammation
or degeneration of peripheral nerves (i.e., neuropathy) as well as changes in
behavior and problems with learning, memory, and decisionmaking.

In affluent countries such
as the United States, where other forms of malnutrition are uncommon, thiamine
deficiency and the resulting WKS occur most commonly among alcoholics. To date
there are only a few estimates of how common WKS is among alcoholics. In autopsy
studies, brain abnormalities characteristic of WKS were present in approximately
13 percent of alcoholics (Harper et al. 1988). These abnormalities include lesions
in brain areas called the mamillary bodies, thalamus, hypothalamus, brain stem,
and cerebellum (see figure 1). Other studies have found that only about 20 percent
of alcoholics in whom the presence of WKS was confirmed at autopsy had been
diagnosed with the disorder before death (Harper 1998). Thus, the clinical presentation
is not always easily recognized by physicians; often examination of the brain
at autopsy is required for definitive diagnosis.

Although WKS in developed
countries occurs most commonly among alcoholics, other groups of patients are
also at risk of developing the disease. For example, all people who are malnourished
(e.g., because they are HIV infected or are undergoing cancer chemotherapy)
or who have a metabolic disease leading to impaired thiamine absorption (i.e.,
uptake) or utilization can develop thiamine deficiency. Patients with severe
kidney disease who are undergoing regular dialysis are also prone to encephalopathy,
and a substantial portion of them have been found to suffer from thiamine deficiency
(Hung et al. 2001). Finally, patients who receive intravenous infusions of carbohydrates
(e.g., the sugar dextrose) may experience episodes of thiamine deficiency, particularly
if they are already at risk of receiving inadequate levels of this nutrient
because they are alcoholics, as thiamine is used in the metabolism of those
carbohydrates (see Ferguson et al. 1997).

Cerebellar Degeneration

Considerably more common
than WKS among alcoholics is a condition called cerebellar degeneration, which
typically develops after 10 or more years of heavy drinking (Charness 1993).
In autopsy studies, 40 percent or more of alcoholics showed signs of this condition
(Torvik 1987), which is characterized by shrinkage (i.e., atrophy) of certain
regions of the cerebellum. This brain area is involved primarily in muscle coordination.
It also is increasingly recognized for its role in various aspects of cognitive
and sensory functioning (Parks et al. 2003). Accordingly, cerebellar degeneration
is associated with difficulties in movement coordination and involuntary eye
movements, such as nystagmus. Cerebellar degeneration is found both in alcoholics
with WKS and in those without it, but because WKS patients typically have a
higher degree of cerebellar atrophy, it appears likely that thiamine deficiency
also is the predominant cause of cerebellar degeneration.

The frequent occurrence
of cerebellar degeneration in alcoholics is consistent with studies demonstrating
that the cerebellum is particularly sensitive to the effects of thiamine deficiency.
(For more information on these studies, see the section “Differential
Sensitivity of Various Brain Regions.”) As a result of this particular
susceptibility, the effects of thiamine deficiency would be expected to appear
first in the cerebellum, manifesting as cerebellar degeneration and its associated
symptoms. In a smaller number of patients, the consequences of insufficient
thiamine then would progress to other brain regions and lead to more widespread
brain dysfunction, including alcohol amnestic disorder or alcohol–induced
persisting dementia.

THIAMINE’S
ACTIONS IN THE CELL

To understand the mechanisms
through which thiamine deficiency, whether induced by alcoholism or other causes,
leads to brain damage, one first must understand the normal role of thiamine
in the cell. Investigations of this issue have focused on three enzymes that
require thiamine as a cofactor. These enzymes are called transketolase, pyruvate
dehydrogenase (PDH) and alpha–ketoglutarate dehydrogenase (α–KGDH);
they all participate in the catabolism of sugar molecules (i.e., carbohydrates)
in the body, as described in the following paragraphs. Each of these enzymes
consists of several components that must be assembled to yield the functional
enzyme, and the addition of thiamine is a critical step in this assembly process.
As a result, thiamine deficiency causes suboptimal levels of functional enzymes
in the cell, in addition to interfering with the activity of those enzymes.

Transketolase is an important
enzyme in a biochemical pathway called the pentose phosphate pathway. In this
set of biochemical reactions, a molecule called glucose–6–phosphate,
which is derived from the sugar glucose, is modified by transketolase, yielding
two products—a sugar called ribose–5–phosphate and a molecule
called reduced nicotinamide adenine dinucleotide phosphate (NADPH) (see figure
2). Both of these molecules are essential for the production of numerous other
important molecules in the cell. Ribose–5–phosphate is needed for
the synthesis of nucleic acids, complex sugar molecules, and other compounds.
NADPH provides hydrogen atoms for chemical reactions that result in the production
of steroids, fatty acids, amino acids, certain neurotransmitters, and other
molecules. In addition, NADPH plays an important role in the synthesis of glutathione,
a compound that is essential in the body’s defense against oxidative stress.
To function properly, all cells require certain levels of NADPH and ribose–5–phosphate,
and the biochemical reaction mediated by transketolase is crucial for maintaining
the appropriate levels of both molecules.

Figure 2
The thiamine–dependent enzyme transketolase is an important enzyme
in the breakdown of glucose through a biochemical pathway called the pentose
phosphate pathway. Glucose is first converted to a molecule called glucose–6–phosphate,
which enters the pentose phosphate pathway where it is further modified
by transketolase. During that reaction, two products are formed—the
sugar ribose–5–phosphate and a molecule called reduced nicotinamide
adenine dinucleotide phosphate (NADPH). Ribose–5–phosphate
is needed for the synthesis of nucleic acids, complex sugar molecules,
and other compounds called coenzymes that are essential for the functioning
of various enzymes. NADPH provides hydrogen atoms for chemical reactions
that result in the production of coenzymes, steroids, fatty acids, amino
acids, and neurotransmitters. In addition, NADPH plays an important role
in the synthesis of glutathione, a compound that is essential to the body’s
defense against damage from oxidative stress. Reduced transketolase activity
interferes with all these essential biochemical processes.

The other two enzymes requiring
thiamine, PDH and α–KGDH, also participate in different steps of
the breakdown and conversion of glucose–6–phosphate through two
consecutive chains of biochemical reactions called glycolysis and the citric
acid cycle (see figure 3). The main function of these pathways is the generation
of a molecule called adenosine triphosphate (ATP), which provides energy for
numerous cellular processes and reactions. Decreases in the activities of PDH
and α–KGDH can result in reduced ATP synthesis, which in turn can
contribute to cell damage and even cell death. In addition, proper functioning
of PDH is essential for the production of the neurotransmitter acetylcholine
as well as for the synthesis of a compound called myelin, which forms a sheath
around the extensions (i.e., axons) of many neurons, thereby ensuring the ability
of these neurons to conduct signals. The citric acid cycle and α–KGDH
play a role in maintaining the levels of the neurotransmitters glutamate, gamma–aminobutyric
acid (GABA), and aspartate, as well as in protein synthesis. Thus, the thiamine–using
enzymes play numerous vital roles in the functioning of cells, and particularly
of neurons.

Figure 3
The thiamine–dependent enzymes pyruvate dehydrogenase (PDH) and
a–ketoglutarate dehydrogenase (α–KGDH) participate in
the metabolism of glucose through two biochemical reactions, glycolysis
and the citric acid cycle. The main function of these two sets of reactions
is to generate adenosine triphosphate (ATP), which provides energy for
the cells. Reduced PDH and α–KGDH activity resulting from thiamine
deficiency can lead to less ATP synthesis, which in turn can contribute
to cell damage and even cell death. In addition, PDH is needed to produce
the neurotransmitter acetylcholine and to generate myelin, a compound
that forms a sheath around the extensions (i.e., axons) of many neurons,
thereby ensuring proper neuronal functioning. The citric acid cycle and
α–KGDH play a role in maintaining the levels of the neurotransmitters
glutamate, gamma–aminobutyric acid (GABA), and aspartate, as well
as in protein synthesis.

When thiamine levels decrease,
the activity levels of all three enzymes are reduced to some extent. The specific
reductions depend both on the enzyme and on the cell type studied (Singleton
and Martin 2001). Overall, transketolase activity may be the most sensitive
measure of thiamine deficiency. Studies using rats found that transketolase
activity may be reduced as much as 90 percent in the brain regions that are
most sensitive to thiamine deficiency (Gibson et al. 1984). Substantial decline
in transketolase activity resulting from thiamine deficiency has even been found
in various brain areas of alcoholics who do not exhibit the clinical and neuropathological
signs of WE (Lavoie and Butterworth 1995), suggesting that thiamine deficiency
can cause adverse effects even before severe brain damage becomes obvious.

Thiamine Uptake
Into the Cell

Thiamine is ingested with
the diet, and to exert its effects in the cells it must be transported from
the gastrointestinal tract to the tissues and cells. This transport involves
at least four steps:

Uptake from the intestine
into the cells that line the intestine

Transport out of those
cells into the bloodstream

Uptake from the blood
into the tissues and cells; for thiamine transported to the brain this also
includes crossing the blood–brain barrier

Transport within the
cells to the areas where the thiamine is needed (e.g., to the cell’s
energy factories, the mitochondria, where PDH and α–KGDH act,
or to the nucleus, where thiamine regulates gene activity).

These transport steps are
accomplished by one or more thiamine transporter molecules. Researchers recently
have identified and cloned the gene for a human thiamine transporter (see Singleton
and Martin 2001). However, the characteristics of the thiamine transport process
differ among different tissues and cell types, suggesting that variants of one
transporter type or even different types of transporters may exist. Indeed,
a second thiamine transporter gene recently has been cloned (Rajgopal et al.
2001). As will be described in more detail in the section “Differential
Sensitivity to Thiamine Deficiency,” subtle variations in the transporter
molecule among cells or among people, resulting in a reduced capacity to transport
thiamine, may contribute to the differential sensitivity to thiamine deficiency.

Once taken up into the cells,
thiamine first is modified by the addition of one or more phosphate groups.
The compound containing two phosphate groups (thiamine diphosphate [ThDP]) is
the actual active molecule that serves as a cofactor for the various thiamine–requiring
enzymes. The levels of phosphate–free thiamine in the cell are relatively
low and are tightly regulated by rapid conversion to the phosphorylated forms.

Mechanisms of
Thiamine Deficiency–Induced Cell Damage

Thiamine deficiency can
lead to cell damage in the central nervous system through several mechanisms.
First, the changes in carbohydrate metabolism, particularly the reduction in
α–KGDH activity, can lead to damage to the mitochondria. Because
the mitochondria produce by far the most energy required for cellular function,
mitochondrial damage can result in cell death through a mechanism called necrosis
(see Singleton and Martin 2001). Second, disturbances associated with thiamine
deficiency in some cell types lead to apoptosis—a form of programmed cell
death (or cell suicide) that serves to remove damaged cells from the organism
(see Singleton and Martin 2001). Third, altered carbohydrate metabolism can
lead to a cellular state called oxidative stress (Calingasan et al. 1999; Todd
and Butterworth 1999), characterized by excess levels of highly reactive molecules
called free radicals and/or the presence of insufficient levels of compounds
to eliminate those free radicals (i.e., antioxidants, such as glutathione).
Oxidative stress can lead to various types of cell damage and even cell death.

ALCOHOL’S
EFFECTS ON THIAMINE UPTAKE AND FUNCTION

As noted earlier, thiamine
deficiency in affluent countries clearly is linked to alcoholism, occurring
in up to 80 percent of alcoholics (e.g., Morgan 1982). However, only a subset
of these alcoholics develop brain disorders such as WKS. Moreover, identical
twins (who share all of their genetic information) show greater similarity with
respect to alcohol–induced brain disease than do fraternal twins (who
share on average 50 percent of their genetic information). These two observations
have led to the conclusion that a genetic predisposition to thiamine deficiency
and its effects may exist, as will be discussed in more detail in the section
“Differential Sensitivity to Thiamine Deficiency.”

Research over the past 30
years has identified several mechanisms through which alcoholism may contribute
to thiamine deficiency. The most important of these mechanisms (as discussed
in Hoyumpa 1980) include:

Inadequate nutritional
intake

Decreased absorption
of thiamine from the gastrointestinal tract and reduced uptake into cells

Impaired utilization
of thiamine in the cells.

Inadequate Nutritional
Intake

Although most people require
a minimum of 0.33 mg thiamine for each 1,000 kcal of energy they consume, alcoholics
tend to consume less than 0.29 mg/1,000 kcal (Woodhill and Nobile 1972). In
fact, in an early study of 3,000 alcoholics admitted to hospitals because of
alcohol withdrawal symptoms or other alcohol–related illnesses, 40 percent
exhibited periodic thiamine deficiency during drinking binges, 25 percent exhibited
prolonged thiamine deficiency with some periods of normal intake, and 35 percent
exhibited continuous thiamine deficiency (Leevy and Baker 1968). A later study
found that alcoholic patients had significantly lower average levels of a thiamine
compound containing one phosphate group (i.e., thiamine monophosphate), but
the average levels of free thiamine and ThDP were similar in alcoholics and
control subjects (Tallaksen et al. 1992). However, some of the alcoholics in
that study had extremely high levels of free thiamine, suggesting that they
may have had a problem in the steps that lead to the conversion of thiamine
into its active, phosphate–containing form.

Decreased Uptake
of Thiamine From the Gastrointestinal Tract

Animal studies have helped
elucidate the mechanisms of normal and alcohol–impaired thiamine uptake
from the gastrointestinal tract into the blood and cells. To be used by the
body, thiamine must cross a number of barriers, first transferring across the
membranes of the cells lining the gut (i.e., enterocytes), then entering those
cells, and then crossing the membranes at the other end of the cells to enter
the bloodstream. At low thiamine concentrations, such as those normally found
in the human body, this transfer is achieved by a specific thiamine transporter
molecule that requires energy. This is called an active transport process and
seems to be associated with the rapid addition of two phosphate groups by the
enzyme thiamine diphosphokinase (TPK) once the thiamine is inside the cell.
At high thiamine concentrations, however, such as can be achieved after additional
thiamine is administered, thiamine transport occurs through a passive process—that
is, a mechanism that requires no energy.

Acute alcohol exposure interferes
with the absorption of thiamine from the gastrointestinal tract at low, but
not at high, thiamine concentrations (Hoyumpa 1980). Furthermore, in studies
using rats, the activity of the TPK enzyme from various tissues decreased with
acute alcohol exposure to about 70 percent of the activity level in control
animals, and with chronic alcohol exposure to about 50 percent (Laforenza et
al. 1990). Although no studies have addressed whether alcohol directly affects
TPK in humans, indirect analyses have found that the ratio of phosphorylated
thiamine (primarily ThDP) to thiamine is significantly lower in alcoholics than
in nonalcoholics (Poupon et al. 1990; Tallaksen et al. 1992)—that is,
that less thiamine is converted to ThDP. This finding suggests that TPK is less
active in the alcoholics.

Thiamine malabsorption could
become clinically significant if combined with the reduced dietary thiamine
intake that is typically found in alcoholics, when other aspects of thiamine
utilization are compromised by alcohol, or when a person requires increased
thiamine amounts because of his or her specific metabolism or condition (e.g.,
in pregnant or lactating women).

Impaired Thiamine
Utilization

The cells’ utilization
of thiamine can be affected in different ways by chronic alcohol use. As mentioned
earlier, once thiamine is imported into the cells, it is first converted into
ThDP by the addition of two phosphate groups. ThDP then binds to the thiamine–using
enzymes, a reaction that requires the presence of magnesium. Chronic alcohol
consumption frequently leads to magnesium deficiency, however (Morgan 1982;
Rindi et al. 1992), which also may contribute to an inadequate functioning of
the thiamine–using enzymes and may cause symptoms resembling those of
thiamine deficiency. In this case, any thiamine that reaches the cells cannot
be used effectively, exacerbating any concurrently existing thiamine deficiency.

Abstinence from alcohol
and improved nutrition have been shown to reverse some of the impairments associated
with thiamine deficiency, including improving brain functioning (Martin et al.
1986). Researchers also administered thiamine to alcoholic patients and laboratory
animals and found that this treatment reversed some of the behavioral and metabolic
consequences of thiamine deficiency (Victor et al. 1989; Lee et al. 1995). Most
recently, researchers administered different thiamine doses for two days to
a group of alcoholics undergoing detoxification, none of whom were diagnosed
with WKS, and then tested the participant’s working memory. These studies
found that participants who received the highest thiamine dose performed best
on tests of working memory (Ambrose et al. 2001).

DIFFERENTIAL SENSITIVITY
TO THIAMINE DEFICIENCY

Differences
in Sensitivity Among People

Several findings suggest
that not all people are equally sensitive to thiamine deficiency and its consequences.
For example, although thiamine deficiency may occur in up to 80 percent of alcoholics
(Tallaksen et al. 1992; Hoyumpa 1980; Morgan 1982), only about 13 percent of
alcoholics develop WKS (Harper et al. 1988). This means that the severest consequences
of thiamine deficiency develop only in a subset of people who consume alcohol
and have poor nutrition on a chronic basis. A possible explanation for this
differential sensitivity is that some people are genetically predisposed to
develop brain damage after experiencing repeated episodes of alcohol–related
thiamine deficiency. To investigate this hypothesis, researchers have studied
the activities of thiamine–using enzymes in patients with and without
Korsakoff’s psychosis, arguing that variants of these enzymes may exist
that could differ in their susceptibility to thiamine deficiency. The results
of these investigations, however, have been inconsistent.2 (2
The studies cited in this section mostly used enzymes isolated from skin or
blood cells of the participants. Although it is not known whether the effects
of thiamine deficiency on these cells are identical to those on brain cells,
the thiamine–using enzymes in these cells should be similar to the enzymes
in brain cells, which are not accessible to the researchers. Using such model
systems to investigate mechanisms of cell function has a long tradition in research.)

One study (Blass and Gibson
1977) compared the activity of transketolase, PDH, and α–KGDH derived
from skin cells of people with and without Korsakoff’s psychosis. These
investigators found that transketolase from the Korsakoff’s patients bound
ThDP less avidly than did the enzyme from the control subjects. Transketolase
from the Korsakoff’s patients could function normally when sufficient
thiamine or ThDP was present; under conditions of thiamine deficiency, however,
the transketolase molecules would not be able to bind enough ThDP to maintain
normal enzyme activity. As a result, the Korsakoff’s patients would be
more susceptible to developing complications of thiamine deficiency than would
people with a transketolase variant that more readily binds ThDP. The investigators
found no differences, however, between Korsakoff’s patients and control
subjects in the ability of the PDH and α–KGDH enzymes to bind ThDP.

In another study (Mukherjee
et al. 1987), researchers studied transketolase activity in alcoholic men without
Korsakoff’s psychosis and their sons who had not yet been exposed to alcohol
(i.e., who were alcohol naive) and compared it with transketolase activity in
nonalcoholic volunteers and their sons. This analysis found that the enzyme
from the alcoholic men and their sons also bound ThDP less strongly than did
the enzyme from the healthy volunteers and their sons (fathers and sons were
similar to each other in both groups). This finding suggests that the genetic
makeup of alcoholics or those who are at risk of becoming alcoholic (e.g., sons
of alcoholics who are still alcohol naive) might cause them to be more affected
by thiamine deficiency than nonalcoholics.

Other investigators, however,
have found no differences in the ability of transketolase from Korsakoff’s
patients and healthy subjects to bind ThDP (Nixon et al. 1984). Several reasons
may explain these differences in findings. For example, if a study includes
active alcoholics, toxic substances formed during alcohol degradation in the
body (e.g., acetaldehyde or oxygen radicals) could conceivably damage the transketolase,
leading to impaired transketolase activity even if the person does not have
a genetic predisposition. Moreover, processing of the samples being studied
could have modified and deactivated the transketolase. Overall, researchers
to date have found no consistent correlation between genetically determined
transketolase variants and a person’s sensitivity to thiamine deficiency
(McCool et al. 1993). To determine whether a genetic predisposition to thiamine
deficiency and resulting brain damage does indeed exist, more detailed molecular
genetic studies are required.

Another possible explanation
for the differences among people in their sensitivity to thiamine deficiency
has focused on the assembly of functional transketolase. To yield a functional
enzyme, two transketolase molecules—each of which is bound to ThDP and
to magnesium—must come together. This assembly step is aided by an as
yet unidentified “assembly factor,” which is probably also involved
in the assembly of other thiamine–using enzymes. If this factor were defective,
the final enzyme complex would be formed at a lower rate and would be unstable
(Wang et al. 1997). Researchers have identified at least one person with WKS
whose cells showed enhanced sensitivity to thiamine deficiency and in whom the
assembly factor was defective (Wang et al. 1997). Other mechanisms that could
contribute to individual differences in the sensitivity to alcoholism could
involve variability in the capacity for thiamine uptake into the cells or in
the overall sensitivity to cell damage induced by oxidative stress.

Differential
Sensitivity of Various Brain Regions

Various brain regions and
even different cell types within one brain region may differ in their sensitivity
to alcohol–induced damage as well as in their susceptibility to associated
problems, including alcohol–related malnutrition (e.g., thiamine deficiency).
For example, as mentioned earlier, the cerebellum appears to be particularly
sensitive to thiamine deficiency, as indicated by the high frequency of cerebellar
degeneration in alcoholics. Autopsy studies have found that a region of the
cerebellum known as the anterior superior cerebellar vermis most frequently
exhibits alcohol–induced damage (Baker et al. 1999). Additional studies
have found that the cerebellar vermis is particularly sensitive to the deleterious
effects of thiamine deficiency (Baker et al. 1999; Lavoie and Butterworth 1995;
Victor et al. 1989). For example, thiamine deficiency contributes to a reduction
in the number and size of a certain cerebellar cell type called Purkinje cells
in parts of the cerebellar vermis (Philips et al. 1987).

The sensitivity of the cerebellum
to alcohol–related damage was confirmed in a recent study in which investigators
used an imaging technique called proton magnetic resonance spectroscopy (proton
MRS) to determine the levels of certain molecules (i.e., metabolites) that reflect
the functionality of the cells in various brain regions of alcoholics and nonalcoholics.
For example, one metabolite reflects nerve cell activity, another metabolite
reflects the degradation and formation (i.e., turnover) of cell membrane components,
and a third metabolite reflects cellular energy levels. The results of the analyses
indicated that these metabolites are significantly reduced in the cerebellum
of alcoholics, more so than in another brain region commonly affected by alcohol,
the frontal white–matter cortex (Parks et al. 2002). Moreover, only some
of these reductions in metabolite levels were reversed when the subjects were
tested again after 3 weeks and then 3 months of abstinence. These findings suggest
that the cerebellum, in particular the cerebellar vermis, is uniquely sensitive
to alcohol’s effects, including alcohol–related thiamine deficiency,
and therefore may be the initial target of alcohol–related damage.

This hypothesis is consistent
with the clinical course of the neurocognitive deficits observed in alcoholics.
Networks of nerve cells (i.e., neural pathways) extend from the cerebellum through
brain regions called the basal ganglia and thalamus to the frontal lobe. These
pathways mediate not only traditional cerebellar functions, such as motor control,
but also perceptual– motor tasks, executive functions, and learning and
memory, all of which are impaired in alcoholics (see Parks et al. 2002). Accordingly,
alcohol–induced damage to the cerebellar vermis could indirectly affect
neurocognitive functions attributed to the frontal lobe, even early in the disease
process when no cortical damage is detectable, by disrupting the neural pathways
connecting the two brain regions. As the alcoholism progresses and alcohol exposure
persists, damage to the frontal lobe is also likely to occur, further interfering
with the functions of that brain region.

In addition to the cerebellum,
numerous other brain regions and structures are damaged in people with WKS.
Although animal studies have suggested that thiamine deficiency may contribute
to damage to these structures, the exact role of thiamine deficiency and the
level of sensitivity of these structures to thiamine deficiency have not yet
been determined. Further studies are certainly needed in this area.

SUMMARY

Thiamine deficiency, which
is found in a large number of alcoholics, is an important contributor to alcohol–related
brain damage of all kinds, not only WKS, as was commonly thought in the past.
Thiamine is an essential cofactor for several enzymes involved in brain cell
metabolism that are required for the production of precursors for several important
cell components as well as for the generation of the energy–supplying
molecule ATP. Thiamine deficiency leads to significant reductions in the activities
of these enzymes, and to deleterious effects on the viability of brain cells.

Chronic alcohol consumption
can cause thiamine deficiency and thus reduced enzyme activity through several
mechanisms, including inadequate dietary intake, malabsorption of thiamine from
the gastrointestinal tract, and impaired utilization of thiamine in the cells.
Accordingly, thiamine deficiency can potentiate a number of processes associated
with chronic alcohol consumption that are toxic to brain cells, as discussed
in other articles in this journal issue. It is important to note that these
adverse effects of alcohol–induced thiamine deficiency, particularly the
reduction of transketolase activity, can occur even in alcoholics who do not
show evidence of WE or WKS.

The extent to which alcohol
exerts its detrimental effects on the brain and various other tissues may be
genetically determined via individual differences in predisposition to thiamine
deficiency disorders. For example, some studies have suggested that there may
be different variants of the genes encoding transketolase, which differ in their
ability to bind the active form of thiamine, particularly at low thiamine concentrations.
Such a genetic variation could be one explanation for why only a subset of alcoholics
who experience thiamine deficiency develop the pathological consequences of
that condition, such as WKS. Additional genetic studies are necessary, however,
to clarify the roles of different genetic variants and determine whether a genetically
determined susceptibility does indeed exist.

Various brain regions also
differ in their sensitivity to alcohol’s effects, including alcohol–induced
thiamine deficiency. The cerebellum appears to be particularly sensitive to
the effects of thiamine deficiency and is the region most frequently damaged
in association with chronic alcohol consumption. This heightened susceptibility
is consistent with the cognitive deficits typically associated with alcoholism.
These deficits are indicative either of cerebellar damage or of damage to the
frontal lobes, which are connected to the cerebellum through neural pathways.
Accordingly, reversal of thiamine deficiency—for example, by administering
thiamine at pharmacological levels—may not only ameliorate the consequences
of cerebellar damage but improve some brain functions typically associated with
the frontal lobe.

LAFORENZA, U.; PATRINI,
C.; GASTALDI, G.; and RINDI, G. Effects of acute and chronic ethanol administration
on thiamine metabolizing enzymes in some brain areas and in other organs of
the rat. Alcohol and Alcoholism 25:591–603, 1990.

LAVOIE, J., and BUTTERWORTH,
R.F. Related activities of thiamine–dependent enzymes in brains of alcoholics
in the absence of Wernicke’s encephalopathy. Alcoholism: Clinical
and Experimental Research 19:1073–1077, 1995.

WOODHILL, J.M., and NOBILE,
S. Thiamine in the 1970 Australian diet with special reference to cereals and
the assessment of thiamine status. International Journal of Vitamin and
Nutrition Research 42:435–443, 1972.